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Genomic Profile of Copy Number Variants on the Short Arm of Human

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Genomic Profile of Copy Number Variants on the Short Arm of Human European Journal of Human Genetics (2010) 18, 1114–1120 & 2010 Macmillan Publishers Limited All rights reserved 1018-4813/10 www.nature.com/ejhg ARTICLE Genomic profile of copy number variants on the short arm of human chromosome 8 Shihui Yu*,1, Stephanie Fiedler1, Andrew Stegner1 and William D Graf2 We evaluated 966 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and found 10 individuals with pathogenic copy number variants (CNVs) on the short arm of chromosome 8 (8p), representing approximately 1% of the patients analyzed. Two patients with 8p terminal deletion associated with interstitial inverted duplication (inv dup del(8p)) had different mechanisms leading to the formation of a dicentric intermediate during meiosis. Three probands carried an identical B5.0 Mb interstitial duplication of chromosome 8p23.1. Four possible hotspots within 8p were observed at nucleotide coordinates of B10.45, 24.32–24.82, 32.19–32.77, and 38.94–39.72 Mb involving the formation of recurrent genomic rearrangements. Other CNVs with deletion- or duplication- specific start or stop coordinates on the 8p provide useful information for exploring the basic mechanisms of complex structural rearrangements in the human genome. European Journal of Human Genetics (2010) 18, 1114–1120; doi:10.1038/ejhg.2010.66; published online 12 May 2010 Keywords: microarray-based comparative genomic hybridization; short arm of chromosome 8; copy number variant; genomic disorders INTRODUCTION MATERIALS AND METHODS The short arm of human chromosome 8 (8p) spans about 44 million Specimen acquisition base pairs containing 484 annotated genes (NCBI Build 36.3 of The DNA samples used for this research study came from 966 consecutive the human genome).1 Point mutations in more than 50 genes on pediatric patients referred for genome-wide screen testing by aCGH in our the 8p are associated with various genetic disorders and diseases laboratory. Each patient was evaluated because of one or more of the following (http://www.ncbi.nlm.nih.gov/omim). categorical clinical findings: global developmental delay, autism, dysmorphism, 8p is especially prone to various genomic rearrangements mainly seizures, or multiple congenital anomalies. The study protocol was approved by the institutional review board of Children’s Mercy Hospitals and Clinics. because of the existence of the two olfactory receptor gene clusters (REPD and REPP) flanking an B5 Mb region of 8p23.1.2–6 These Testing using chromosome banding analysis (GTG banding) and REPD- and/or REPP-related 8p genomic rearrangements include fluorescence in situ hybridization technique (1) the 8p23.1 deletion or duplication between REPD and REPP,6–9 8,10 Standard GTG banding analyses were performed on the peripheral blood (2) the 8p23.1 paracentric inversion between REPD and REPP, previously (patients 2, 3, 4, 6, 8, and 10) or concurrently (patients 1, 5 and 7, (3) the pericentric inversion (inv(8)(p23.1q22.1)) and recombinant 8, 9), and on the cultured skin fibroblast cells (patient 10). Fluorescence in situ 11 chromosome 8 (rec(8)dup(8q)inv(8)(p23.1q22.1)), (4) the 8p inter- hybridization (FISH) tests were performed for patient 3 using an 8p sub- stitial inverted duplication with associated terminal deletion (inv dup telomeric probe (AFM 197XG5), and for patient 10 using a chromosome 8 del(8p)),5,6,8,10,12–24 (5) the 8p translocations involving the 8p23.1,25,26 centromeric probe (CEP 8) as recommended by the manufacturer (Abbott and (6) different types of supernumerary chromosome 8 (SMC(8)) Molecular Inc., Des Plaines, IL, USA). involving the breakpoints within 8p23.1.4,27 In addition to these defined 8p genomic abnormalities, other pathogenic genomic changes Testing using microarray-based comparative genomic hybridization have been identified,28–30 whereas numerous genomic imbalances on The aCGH platform used in this study is the Agilent Human Genome 8p are still described as copy number variants (CNVs) of unknown Microarray Kit 244K, a genome-wide screening platform, containing 10 960 distinct 60-mer oligonucleotide probes on chromosome 8, with average probe clinical significance or CNVs without apparent clinical significance spacing of 13.3 kb (Agilent Technologies, Santa Clara, CA, USA). All aCGH (benign CNVs) (http://projects.tcag.ca/variation). tests were performed and analyzed following the protocols described In this study, we describe a comprehensive CNV profile of 8p previously.31 derived from the tests of a large number of pediatric patients with diverse clinical phenotypes using a high-resolution microarray- aCGH result verification and parental follow-up based comparative genomic hybridization (aCGH) platform, and The GTG banding analysis results for patients 1, 2, 3, 7, and 10 and FISH results discuss plausible mechanisms for the formation of these genomic for patients 2, 3, and 10 were used for verification of the abnormal aCGH rearrangements. findings on 8p (Table 1; Supplementary Figure S1). Quantitative real-time PCR 1Department of Pathology, Children’s Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA; 2Section of Neurology, Children’s Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA *Correspondence: Dr S Yu, Department of Pathology, Children’s Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA. Tel: +1 816 346 1303; Fax: +1 816 802 1204; E-mail: [email protected] Received 17 November 2009; revised 1 April 2010; accepted 1 April 2010; published online 12 May 2010 Genomic profile of CNVs on the short arm of 8p SYuet al 1115 Table 1 Pathogenic CNVs on the short arm of chromosome 8 Chromosome and FISH Start Stop Verification for Patient findings aCGH findings coordinate (bp) coordinate (bp) Size (bp) aCGH findings Parents availability, and test findings 1 46,XY,del(8)(p23.1) [C] 8p23.3p23.1Â1 1 10 453 863 10 453 862 GTG banding Both parents, normal findings by GTG banding 2 46,XY,add(8)(p12).ish 8p23.3p23.1Â1 1 6929891 6929890 GTG banding, Both parents, normal findings add(8)(P12)(wcp8+) [R] 8p23.1p21.2Â3 12 601 939 24 823 981 12 222 042 FISH and by GTG banding 8q24.3Â3 145 084 438 146 265 046 1180608 qPCR 3 46,XX,add(8)(p23.1).ish 8p23.3p23.1Â1 1 6913476 6913475 GTG banding, Both parents, normal findings add(8)(p23.1)(8pterÀ)[R] 8p23.1p21.2Â3 7358840 25 707 713 18 348 873 FISH and by GTG banding and qPCR qPCR 4 46,XX [R] 8p23.1Â3 7 256 029 11 898 119 4 642 090 qPCR Inherited from mother; father NA 5 46,XY,dup(8)(p23.1p23.2) [C] 8p23.1Â3 7 256 029 12 512 055 5 256 026 qPCR Both parents, normal findings by qPCR 6 46,XY,var(8)(p23.1p23.2) [R] 8p23.1Â3 7 358 840 11 904 101 4 545 261 qPCR Mother normal by qPCR; father NA 7 46,XY,del(8)(p12p22) [C] 8p22p12Â1 18 375 250 32 765 636 14 390 386 GTG banding Both parents, normal findings by GTG banding 8 46,XX,t(8;18;14) 2q35q36.1Â1 217 249 378 222 041 732 4792354 qPCR Both parents, normal findings (p21.3;q23.1; q24.1) [R] 4q35.2Â1 188 428 673 189 965 537 1536864 by GTG banding and qPCR 8p21.3p21.2Â1 22 680 632 24 395 832 1715200 14q22.2Â1 54 012 870 54 614 836 601 966 9 46,XY [C] 8p12Â1 32 189 595 35 280 851 3 091 256 qPCR Both parents, inherited from father 10 47,XY,+mar.ish mar(8) 8p11.23q11.1Â3 38 944 542 47 575 850 8 631 308 GTG banding Both parents, normal findings (D8Z2+) from blood; and FISH by GTG banding 47,XY,+mar[20]/46,XY[7] from skin [R] Abbreviations: C, concurrent chromosome analysis; R, retrospective chromosome analysis; Dup/Del, duplication/deletion; NA, not available. (qPCR) were performed as previously described for verification of some and 3 have an B6.90 Mb terminal deletion of 8p with the breakpoints abnormal aCGH findings on 8p using different test primers targeting genes residing within the REPD region. The distal breakpoints of the within corresponding abnormal regions (RECQL4 for patient 1, GATA4 gene 8p23.1p21.2 duplications reside within REPP in patient 2 and REPD for patients 2-6, DLC1 gene for patient 3, NKX3 gene for patient 8, and MAK16 in patient 3, respectively. Three patients (4, 5, and 6) have an B5.0 Mb 32 for patient 9 (Table 1; Supplementary Table S1)). GTG banding, FISH, or interstitial duplication of 8p23.1 flanked by REPD and REPP (Figure 1; qPCR was also carried out for available corresponding parental follow-up Supplementary Figure S2b). The proximal breakpoint of the 14.39 Mb studies in this study (Table 1). deletion in patient 7, and the distal breakpoint of the 3.09 Mb deletion in patient 9 all reside within Neuregulin 1 (NRG1) gene within the RESULTS 8p11.23 region (Figure 1; Supplementary Figure S2c). aCGH testing Results from GTG banding and FISH testing identified four cryptic de novo deletions in four chromosomes in The GTG banding and FISH testing results are summarized in Table 1. patient 8 (Supplementary Figure S1c), including one of them with Of the 10 patients with abnormal aCGH results, 2 showed normal involvement of 8p21.3p21.2 (Figure 1; Supplementary Figure S2c). karyotypes (patients 4 and 9) and the remaining patients appeared to Patient 10 has a de novo mosaic pericentric SMC(8) (47,XY,+mar[20]/ have chromosomal rearrangements (Table 1). Images from GTG 46,XY[7]) (Supplementary Figure S1d).
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